Acute low-back pain and the associated disability represent a national health problem of crisis proportions. While the etiology of back pain is varied, in many patients it is clinically associated with derangement of the intervertebral disc and disruption of the annulus fibrosus (a key structural tissue of the disc). Consequently, potential techniques to repair or replace the disc, or portions thereof, are generating increasing clinical interest. However, this treatment path is limited due to lack of robust constitutive models and structure/ function relationships for the annulus fibrosus. In particular, there is no validated constitutive relationship that can predict the three-dimensional response of the degenerating annulus. Also, there is no clear understanding regarding how biochemical and architectural features of the annulus contribute to its material response. These data are critical to understand how a patients existing tissue can support mechanical function of bioengineered implants, and to define success of tissue engineering approaches for replacement or repair. Our overall hypothesis that annular biomechanical properties can be quantitatively related to structural features at the molecular level. To test this hypothesis, we propose to first establish a degeneration-dependent constitutive model capable of predicting the response of the annulus to complex deformations. Next, we propose to analyze the composition and post-translational modifications of the annular macromolecules. In addition, a novel imaging technique -harmonic generation- will be used to study the molecular architecture. Next, we will utilize our established statistical methodologies to define structure/ function relationships between the biomechanical, biochemical and architectural data. Finally, we will validate these structure/ function relationships by testing an independent set of disc samples first as harvested, then after modification under controlled in vitro conditions to produce specific molecular alterations that mimic degenerative changes.